Enalapril, structure

Enalapril (structure in scheme 196) is an angiotensinconverting enzyme (ACE) inhibitor for the control of hypertension. 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

Captopril 678 and enalapril 679 are potent angiotensin converting enzyme (ACE) inhibitors used as antihypertensives. Molecular manipulation based on the enzyme model led to the discovery of some perspective bicyclic structures, for example, cilazapril 680 and compound 681, highly active antihypertensives in vivo. Compound 681 belongs to the most potent conformationally restricted ACE inhibitors and is often used as a model for molecular modeling studies <1996JA8231>. 

An important class of orally active ACE inhibitors, directed against the active site of ACE, is now extensively used. Captopril and enalapril are examples of the many potent ACE inhibitors that are available. These drugs differ in their structure and pharmacokinetics, but in clinical use, they are interchangeable. ACE inhibitors decrease systemic vascular resistance without increasing heart rate, and they promote natriuresis. As described in Chapters 11 and 13, they are effective in the treatment of hypertension, decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction, and delay the progression of diabetic nephropathy. 

Rizzoni, D., Ported, E., Piccoli, A., et al. 1998. Effects of losartan and enalapril on small artery structure in hypertensive rats. Hypertension 32 305-310. 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

Trandolapril. Trandolapril, l-(2-(l-ethoxycarbonyl-3-phenylpropylumino)propionyl oc(ahydroindole-2-curboxylic acid (Mavik), is an indole-containing ACE inhibitor that is structurally related to most of the agents discussed above. Enalapril is very similar to (randolapril. with (he primary difference occurring in (he heterocyclic sy.stems. The... 

ACE inhibitor drugs were developed by modelling interaction with the active site of the enzyme of a snake-venom-derived bradykinin-potentiating peptide, and from this the necessary structure of non-peptide inhibitors was inferred. The first such ACE inhibitor used medicinally was caplopril. Later examples in clinical use include cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril. Several ACE inhibitors are now administered clinically as prodrugs - which have good bioavailability, but are inactive in their own right. They are then converted to the active molecule in vivo, usually by esterases (e.g. enalapril to enalaprilat. and ramipril to ramiprilat). 

FIGURE 6.24 Structures of some key compounds in the development of captopril and enalapril. " ... 

Not all polymorphism originates from conformational requirements, and many polymorphic situations exist because of different modes of molecular packing in the solid-state structures. For example, the two polymorphs of enalapril maleate exhibit very similar molecular conformations (as evidenced by the similarity in spectral characteristics), and the observed differences in crystal structure, therefore, are attributed to different modes of crystal packing. Sufficient differences in the solid-state C-NMR spectra of the four polymorphs of sulfathiazole were observed to enable the use of this technique as an analytical tool, but these differences could not be ascribed to differences in molecular conformations among the polymorphs. ... 

Figure 8.7. Molecular structure of the ACE-inhib-itors enalapril, enalaprilat, and lisinopril. Enalapril and lisinopril are substrates for PepTl.

Despite excellent IV activity, enalaprilat has very poor oral bioavailability. Esterification of enalaprilat produced enalapril (Fig. 28.9), a compound with superior oral bioavailability. The combination of structural features in enalaprilat, especially the two carboxylate groups and the secondary amine, are responsible for its overall low lipophilicity and poor oral bioavailability. Zwitterion formation also has been suggested to contribute to the low oral activity (25), and a comparison of the pKa values for the secondary amine of enalaprilat and enalapril supports this explanation. Ionization of the adjacent carboxylate in enalaprilat greatly enhances the basicity of the secondary amine such that the pKa of the amine in this compound is 8.02, whereas in enalapril, it is only 5.49. Thus, in the small intestine, the amine in enalaprilat will be primarily ionized and form a zwitterion with the adjacent carboxylate, but the amine in enalapril will be primarily un-ionized (26). 

The commercially most successful zinc(II) carboxylase inhibitors include captopril (1), enalapril (2a), enalaprilat (2b) (the diacid metabolite of 2a), and trandolapril (3).i55-i58,i60-i62 or structures of these drugs, see Scheme 15. They all act against the ACE that converts angiotensin I to angiotensin II. These compounds have been used for years as successful orally active drugs to reduce high blood pressure by decreasing the ACE activities that play a major role in the... 

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